Musculoskeletal pain in Parkinson's disease: Association with dopaminergic deficiency in the caudate nucleus

Musculoskeletal (MSK) pain affects over 80% of People with Parkinson's (PD, PwP) and may, in part, be dopaminergic in origin, as dopaminergic medication often leads to its relief.


| INTRODUCTION
Parkinson's disease (PD) affects over 8.5 million people globally.Fueled by population ageing, prolonged life expectancy, declining smoking rates and increasing industrialization, this number is rising sharply (Dorsey et al., 2018).Musculoskeletal (MSK) pain affects over 80% of those individuals, with weighty healthcare and socioeconomic consequences (Ghosh et al., 2020;Rukavina et al., 2022).Throughout the course of PD, the risk to develop MSK pain is significantly elevated in People with Parkinson's (PwP), compared with healthy individuals (Lien et al., 2017).MSK pain can also occur as a prodromal complaint of PD, prior to the onset of motor features (Farnikova et al., 2012).
Causative mechanisms underlying MSK pain in PwP are several and may overlap: while PD motor symptoms (bradykinesia, rigidity, tremor, postural abnormalities) and/or comorbidities (for example, osteoarthritis or osteopenia) may give rise to MSK pain, it is, in part, also underpinned by the impact of PD-specific neurodegeneration on distinct neural circuits involved in nociceptive processing (Blanchet & Brefel-Courbon, 2018;Lawn et al., 2021;Rukavina et al., 2019;Rukavina, Cummins, et al., 2021).
Progressive neurodegeneration of substantia nigra neurons and altered striatal dopaminergic neurotransmission are neuropathological hallmarks of PD.In health, dopamine is implicated in the top-down cognitive and affective modulation of pain, while dysfunctional dopaminergic neurotransmission has been associated with the development and maintenance of chronic pain (Martin et al., 2022).In PD, pain and dopaminergic neurotransmission are closely linked and the potential analgesic effect of dopamine for PD-related pain has been noted in both experimental and clinical conditions (Grigoriou et al., 2021;Rukavina, Batzu, et al., 2021).Among different subtypes of pain PwP may experience, this is particularly evident for PD-related MSK pain, which is dopamine-responsive in most affected individuals (Farnikova et al., 2012;Li et al., 2021).
Striatal dopamine transporter (DaT) visualization with a radiopharmaceutical DaTscan™ ( 123 I-Ioflupane Injection) using single-photon emission computed tomography (SPECT) brain imaging is a helpful diagnostic tool widely used in clinical practice to detect and quantify nigrostriatal dopaminergic depletion and facilitate the differential diagnosis of neurodegenerative PD vs. non-dopamine deficiency aetiologias of Parkinsonism (Bega et al., 2021).In a research setting, the degree of striatal dopaminergic deficiency, measured by putaminal, the caudate nucleus or striatal binding ratios, has been associated with the severity of motor symptoms of PD and with global measures of disease severity, as well as with certain nonmotor symptoms (NMS) (Jeong et al., 2021(Jeong et al., , 2022;;Pirker, 2003;Qamar et al., 2017).However, its link with PD-related pain, and specifically MSK pain in PD, is unclear.
We hypothesised that, given its possible dopaminergic basis, striatal DaT binding ratios may serve as a surrogate marker for MSK pain in PwP.

| METHODS
PwP who underwent DaTscan™ as a part of their clinicaldiagnostic work up at the Parkinson's Foundation Centre of Excellence at King's College Hospital NHS Foundation Trust, London, United Kingdom (UK) were, after giving informed consent, enrolled in the "Non-motor International Longitudinal Study" (NILS; UK National Institute for Health Research Clinical Research Network Number 10084; ethical approval: NRES SouthEast London REC3, 1008410/H0808/141) and are included in this exploratory cross-sectional analysis.Patients with pain (acute or chronic) better accounted for by any aetiology other than PD (as determined by their treating neurologists based on clinical examination and medical history), were not enrolled.NILS is a multicentre, international study (including 34 centres worldwide), in which repeated evaluations using validated clinical assessment tools are performed in 6-monthly or yearly periods with an aim to gain insight and enhance the understanding of the range and natural history of NMS, including pain, in PD.As a part of the NILS study informed consent process, all participants consented for their imaging data to be used for research purposes.Socio-demographic (age, gender, ethnicity) and disease-specific (disease duration (DD), current medication) features were noted from the NILS database.Levodopa Equivalent Daily Dose (LEDD) was calculated as reported previously (Schade et al., 2020).
Clinical assessments included: King's Parkinson's Disease Pain Scale-A raterinterview-based scale with seven domains, which subclassifies PD-related pain into seven distinctive subtypes (musculoskeletal, chronic, fluctuation-related, nocturnal, oro-facial, discoloration and oedema/swelling, and radicular pain) and rates their severity and frequency over the past month (Chaudhuri et al., 2015).This is the first PDspecific pain scale, and has, since its validation, been used in numerous observational and interventional (pharmacological and non-pharmacological) studies globally.The International Parkinson and Movement Disorders Society (MDS) recommends the use of the KPPS for the assessment of pain intensity in PD (Perez-Lloret et al., 2016).
Hoehn & Yahr (H&Y) stage-A simple, five-point descriptive scale designed for grading the severity of PD.Based on clinical examination, rater classifies the extent of patient's impairment and disability into one of five stages (H&Y I-V): unilateral disease (H&Y Stage I), bilateral disease with intact balance (H&Y Stage II), the presence of postural instability (H&Y Stage III), loss of physical independence (H&Y Stage IV), and being wheelchair-or bedbound (H&Y Stage V) (Hoehn & Yahr, 1967).
Parkinson's Disease Questionnaire-Short Form (PDQ-8)-An eight-item patient-completed questionnaire used to quantify self-perceived health in individuals with PD.Patients rate each item with scores from 0 ("never") to 4 ("always" or "cannot do at all").Finally, the single index (PDQ-8 SI) is calculated by summing the eight items of the PDQ-8 and then standardizing the score on a scale of 0 to 100 (Jenkinson et al., 1997).
Specific DaTscan binding ratios were analysed for each striatum, and its two sub-regions-the caudate nucleus and putamen (striatal and sub-regional binding ratios, SBR).To account for age-expected decrease in striatal binding, z-scores were derived normalizing the images to age and gendermatched healthy controls from the European-Databaseof-DaTscan-of-healthy-controls (ENC-DAT) (EMA, 2010;Varrone et al., 2013).The "more affected" side, defined as a side with lower z-scores, was used in the analysis.
Statistical analysis was carried out using SPSS Statistics software, version 26 (IBM).Normality of data distribution was tested (One-sample Kolmogorov-Smirnov test) and descriptive statistics provided.Depending on the normality of the distribution, data is shown as mean ± standard deviation or median (range).To assess the betweengroup differences, Independent Samples t-Test or Mann-Whitney test were used as appropriate.The Chi-squared test was used when comparing categorical variables.First, we ran a set of univariate logistic regression models to explore the impact of distinctive DaT-uptake z-scores on the presence of MSK pain.z-scores for striatal, putamen and the caudate nucleus binding ratios (of the more affected side), as well as additional possible confounding variables (DD, LEDD, H&Y, the time between the DaTscan and the assessment and the time between the diagnosis and the DaTscan) were entered into univariate logistic regression models.Next, statistically significant determinants of MSK pain identified in the univariate logistic regression analysis were included in the multivariate logistic regression analysis where, to control for possible cofounders, we also included DD, H&Y and LEDD as additional independent variables.Spearman's correlation analysis was conducted to investigate the association of MSK pain with the severity of motor symptoms (SCOPA-Motor total score) and the self-declared health-related quality of life (PDQ-8 SI).Statistical significance was set to 0.05.
Mean z-scores for SBR in striatum, the caudate nucleus and putamen on the more affected side were −3.53 ± 0.72, −2.96 ± 0.82 and −3.98 ± 0.63, respectively.The z-scores for SBR differed significantly between the more and the less affected striatum (difference mean −0.71 ± 0.50, <0.001) the more and the less affected caudate nucleus (difference mean −0.68 ± 0.45, <0.001) and the more and the less affected putamen (difference mean −0.77 ± 0.58, <0.001) and there was a statistically significant difference in mean z-scores for SBR between putamen and the caudate nucleus (difference mean −0.97 ± 0.42, <0.001).
Mean KPPS total score was 12.66 ± 11.68.MSK pain (KPPS; Item 1, Domain 1 score ≥1) was identified as the most prevalent pain subtype, declared by 71.7% of the participants, with mean KPPS Item 1 score 5.34 ± 4.76.Figure 1.MSK pain did not correlate with the severity of motor symptoms (SCOPA-Motor total score; p = 0.783), but there was a significant correlation with quality of life, measured using PDQ-8 (r s = 0.290, p = 0.035).
There were no statistically significant differences between the group of patients affected by MSK pain (n = 38) and the non-affected group (n = 15) in terms of age, sex, disease duration, H&Y stage, LEDD or SCOPA-Motor total score.Total burden of pain, self-reported on the KPPS, was higher in participants with MSK pain.Table 1.
Patients suffering from MSK pain had significantly lower z-scores for SBR for striatum (−3.67 ± 0.68 vs. −3.18± 0.70, p = 0.024) and, more specifically, for the caudate nucleus (−3.12 ± 0.77 vs. −2.55± 0.80, p = 0.021) on the more affected side, while the z-scores for putamen did not differ significantly between the two groups.Table 2.
Statistically significant determinants of MSK pain identified in the univariate regression analysis were entered in multivariate regression models.Here, after the adjustment for DD, H&Y and LEDD, z-scores for the more affected striatum (Exp (B) = 0.338, 95% CI for Exp (B) 0.123-0.931,p = 0.036; Figure 2a) and the more affected caudate nucleus (Exp (B) = 0.367, 95% CI for Exp (B) 0.148-0.910,p = 0.031; Figure 2b) were statistically significant predictors of MSK pain.

CONCLUSIONS
In this cross-sectional analysis, we explored a potential link between the burden of MSK pain in PwP and the degree of striatal dopaminergic depletion.

Our key findings are:
1.There is a significant association between clinical ratings for MSK pain gathered using the KPPS and the diminished DaT availability in striatum-more specifically, in the caudate nucleus, visualized using the DaTscan™.Even after the adjustment for other relevant clinical features (DD, H&Y and LEDD), this association retained statistical significance.2. The severity of MSK pain in PwP does not correlate with the motor symptom burden.
The above observations merit discussion which is presented in the following paragraphs.Similarly to our  *Statistically significant differences (p < 0.05).

T A B L E 2
Comparison of z-scores for striatal and sub-regional binding ratios between the group with the PD-related musculoskeletal pain (MSK pain+) and the group without (MSK pain−).findings, previous studies also identified MSK pain as the most frequent subtype of PD-related pain (Ghosh et al., 2020).While, in general, MSK pain in PwP is considered to arise secondary to mechanical problems and skeletal abnormalities, it seems to be markedly alleviated by pharmacological modulation of dopaminergic neurotransmission.In previous studies, 85% of PwP experienced MSK pain relief following levodopa intake (Farnikova et al., 2012), with a reduction in its intensity (on a 11-point numeric scale) of up to 83% (Li et al., 2021).Furthermore, the severity of MSK pain may fluctuate in line with levodopa induced motor fluctuations, improving during "on" and worsening during "off" periods (Rizos et al., 2014;Storch et al., 2013).Here, in agreement with those observations, we have demonstrated that, in PwP, MSK pain does not simply correlate with the severity of motor deficits, but is related to the degree of striatal, especially the caudate nucleus, dopaminergic deficiency.Evidence from both animal and human studies indicates that striatal dopamine D2 and D3 receptors (DA D2/ D3R) govern dopaminergic pain control at the cerebral level (Martikainen et al., 2018).In health, DA neurotransmission via D2/D3R in the dorsal striatum is involved in both sensory and affective aspects of the individual pain experience, contributing to processing in the pain neuraxis via, among others, endogenous opioidergic (μopioid receptor)-mediated mechanisms (Martikainen et al., 2015).For example, certain polymorphisms of the DA D2R predict individual's sensitivity to noxious and innocuous thermal stimuli (Jääskeläinen et al., 2014).In PD-free individuals, recent evidence links inter-individual variability in striatal DA D2/D3R neurotransmission and the development and maintenance of generalized hyperalgesia in chronic MSK pain, in a manner that is specific to fibromyalgia and chronic back pain (Martikainen et al., 2015).
A link between precisely classified (using validated clinical assessment tools) PD-related pain and striatal DaT imaging has not been probed previously.Meanwhile, it has been well documented that, overall, striatal DaT availability correlates with the burden of parkinsonian motor symptoms and that striatal DaT binding decreases progressively with the progression of PD (Pirker, 2003).In particular, dopamine deficiency in the posterior putamen has been indicated as a key determinant of the severity of motor deficits (measured using the Unified PD Rating Scale Part III (UPDRS III) both in drug-naïve patients with early stages of PD (Jeong et al., 2022), as well as in those receiving dopaminergic treatment, regardless of the age at the disease onset (Liu et al., 2015).Regarding NMS, severity of both anxiety and depression (measured using the State-Trait Anxiety Inventory (STAI) and Profile of Mood States Scale-POMS tension subscale) correlate with decreased DaT availability in the left anterior putamen (Weintraub et al., 2005).
In our cohort, striatal dopaminergic neurodegeneration followed a typical pattern, with asymmetrical posterior-to-anterior gradient, more severely involving putamen, while relatively sparing the caudate nucleus (Pasquini et al., 2019).Of note, our data revealed a significant association between the 123 I-ioflupane tracer uptake loss in the caudate nucleus and MSK pain, indicating a greater preferential involvement of the caudate nucleus in the development and maintenance of PD-related MSK pain.While the putamen is a part of a cortical-subcortical neuronal loop with a predominantly motor function, the caudate nucleus receives input from the frontal association cortex, limbic system and other neocortical areas showing a nonmotor functional focus.In addition to planning and execution of movements, the caudate nucleus is also involved in a range of complex and behavioural functions, including, but not limited to, learning, memory, reward, motivation, emotion and romantic interaction (Carbon et al., 2004;Driscoll et al., 2022;Liu et al., 2015;Pasquini et al., 2019).A link between the caudate nucleus function and pain has been noted previously, as avoidance and nocifensive behaviours are also mediated by the caudate nucleus, which integrates incoming nociceptive input to generate coordinated and spatially guided motor responses (Blanchet & Brefel-Courbon, 2018).Furthermore, functional magnetic resonance imaging (fMRI) studies suggest an activation of the caudate nucleus related to spatial discrimination (comparing the spatial location of an incoming noxious heat stimulus with that of a previously experienced stimulus), to suppression of painful stimuli and the anticipation of pain (Oshiro et al., 2007;Wunderlich et al., 2011).In the caudate nucleus of patients with chronic non-neuropathic lower back pain, the baseline DA D2/D3R expression and their experimental pain-induced activation are both significantly reduced in comparison with healthy controls (Martikainen et al., 2015).It is thus possible that the caudate nucleus may be implicated in the pathophysiology of MSK pain in PwP.As recent evidence suggests that the caudate nucleus dopaminergic dysfunction is not uncommon in PwP as early as at the disease onset (Pasquini et al., 2019), it may possibly, in the future, serve as a clinical neuroimaging marker which may, early in the course of the disease, aid the recognition of patients predisposed the development of chronic MSK pain.
Certain limitations of our study need to be acknowledged.Due to its exploratory, pilot nature and gathering of "real-life" neuroimaging data obtained in the course of the clinical diagnostic work up, the sample size could not be estimated a priori and (particularly for the group without the MSK pain) remains rather limited.For the same reason, although several NMS frequently present in PwP (including, for example, anxiety, depression, sleep disturbances and cognitive complaints) may aggravate pain burden, we have chosen not to add up those features in the analysis, as the study's sample size would not allow for any accurate conclusions to be drawn.Of note, here, we assessed PD-related pain present over the past month, while the International Classification of Diseases, Eleventh Revision (ICD-11) and The International Association for Study of Pain define chronic pain as pain that persists or recurs for longer than 3 months (ICD-11, 2019).Despite this, the use of validated clinical assessment tools, coupled with a real-life biomarker sets our study apart, and its findings (pending a confirmation in larger studies) may have far-reaching implications for clinical practice, potentially facilitating the recognition of MSK pain in PwP.
To conclude, our findings suggest a plausible link between the MSK pain in PwP and the severity of striatal dopaminergic deficiency, specifically in the caudate nucleus.Of note, MSK pain appears to be unaffected by the severity of motor symptoms burden, contrary to commonly held views.High-quality, prospective studies in enriched populations are needed to establish whether DaT availability in the caudate nucleus might serve as a useful marker for MSK pain in PD, identifying those at risk and allowing for an early delivery of precise, pain sub-type specific and individually tailored painrelieving strategies.

ACKNO WLE DGE MENTS
We are thankful to all participants with Parkinson's disease, their families and caregivers, who dedicated their time to contribute to this project and would like to acknowledge the efforts of the staff at the Department of Nuclear medicine, and the research team at the Parkinson's Foundation Centre of Excellence (Director: Prof K Ray Chaudhuri) at the King's College Hospital NHS Foundation Trust, London, United Kingdom.
Comparison of demographic and clinical characteristics between the group with musculoskeletal PD-related pain (MSK Pain+) and without (MSK Pain−).Data are shown as mean ± standard deviation.

F
Percentage of patients with Parkinson's disease (PD) who declared distinctive subtypes of PD-related pain, as assessed by the King's Parkinson's Disease Pain Scale.
Design: Katarina Rukavina and K. Ray Chaudhuri.Execution, data collection: Katarina Rukavina, Nicola Mulholland, Ben Corcoran, Juliet Staunton, Pavlos Zinzalias, Kit Wu, Alexandra Rizos.Analysis: Katarina Rukavina, Magdalena Krbot Skoric.Writing of the first draft: Katarina Rukavina.Discussing results and editing of final version of the manuscript: All authors.